Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey

Abstract

Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.

The TNF Paradox in Cancer Progression and Immunotherapy

“…The impact anti-TNF antibodies have on anti-cancer immune responses in these settings are not known. A recent study indicates that 1% of patients with advanced melanoma treated by ICI develop severe colitis, which can be efficiently cured with one infliximab infusion in most of the patients, without affecting disease outcome (32). A clinical study evaluating the tolerability of infliximab in advanced cancer patients shows no dose-limiting toxic (DLT) effects and no evidence of disease acceleration in any patient.…”

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…The irAEs, i.g. colitis, are managed by corticosteroid administration (270,271), but refractory cases are treated with infliximab once ICB is suspended. Considering the aforementioned mechanisms of TNFα-induced ICB resistance, preclinical studies investigated the prophylactic effect of TNFα blockade both to impede irAEs development and to enhance ICB's efficacy.…”

Systematic review with meta‐analysis: effectiveness of anti‐inflammatory therapy in immune checkpoint inhibitor‐induced enterocolitis

“…infliximab treated patients experienced a response, 42 Six studies reported safety outcomes in the context of infliximab 10,25,[36][37][38]40 across 171 infliximab-treated patients. Of 36 infliximab-treated corticosteroid refractory patients, Harding et al describe hypersensitivity reactions in two and a fungal pneumonia in one patient.…”

“…Where dose of infliximab used was defined, it was 5 mg/ kg. 9,13,14,16,[38][39][40] The number of infliximab doses administered was reported in 14 studies, 9,10,13,14,16,25,32,[35][36][37][38][39][40][41] with three of these not included in the quantitative analysis as too few patients were treated.…”